JP2018520657A5

JP2018520657A5 -

Info

Publication number: JP2018520657A5
Application number: JP2017561902A
Authority: JP
Filing date: 2016-05-26
Publication date: 2019-07-04
Anticipated expiration: 2036-05-26

Claims

配列番号８７の配列を含む重鎖可変領域ＣＤＲ１、配列番号３１７の配列を含む重鎖可変領域ＣＤＲ２および配列番号８９の配列を含む重鎖可変領域ＣＤＲ３ならびに配列番号９０の配列を含む軽鎖可変領域ＣＤＲ１、配列番号９１の配列を含む軽鎖可変領域ＣＤＲ２および配列番号９２の配列を含む軽鎖可変領域ＣＤＲ３を含む、ヒトＯＸ４０と結合する単離された抗体。 Sequence of the heavy chain variable region CDR 3 rabbi in SEQ ID NO: 90 comprising the sequence of SEQ heavy chain variable region CDR 1 comprising the sequence of ID NO: 87 comprises the sequence of SEQ ID NO: 317 heavy chain variable region CDR 2 Contact and SEQ ID NO: 89 the light chain variable region CDR 1, comprises a light chain variable region CDR 3 comprising the sequences of the light chain variable region CDR 2 Contact and SEQ ID NO: 92 comprising the sequence of SEQ ID NO: 91 was isolated binds to human OX40 antibodies comprising .

配列番号３１８の配列を含む重鎖可変領域および配列番号９４の配列を含む軽鎖可変領域を含む、ヒトＯＸ４０と結合する単離された抗体。 A light chain variable area comprising the sequence of heavy chain variable area Contact and SEQ ID NO: 94 comprising the sequence of SEQ ID NO: 318, isolated antibody that binds to human OX40.

配列番号１２４の配列を含む重鎖および配列番号１１６の配列を含む軽鎖を含む、ヒトＯＸ４０と結合する単離された抗体。 It comprises a light chain comprising the sequence of heavy chain Contact and SEQ ID NO: 116 comprising the sequence of SEQ ID NO: 124, isolated antibody that binds to human OX40.

重鎖および軽鎖定常領域を含む、請求項１または２に記載の抗体。 The antibody according to claim 1 or 2, comprising heavy and light chain constant regions.

重鎖定常領域が、Ｃ末端リシンを欠くか、またはＣ末端にリシン以外のアミノ酸を含む、請求項１から４のいずれか一項に記載の抗体。 The antibody according to any one of claims 1 to 4, wherein the heavy chain constant region lacks C-terminal lysine or comprises an amino acid other than lysine at the C-terminus.

抗原特異的Ｔ細胞応答を刺激する、請求項１から５のいずれか一項に記載の抗体。 The antibody according to any one of claims 1 to 5, which stimulates an antigen specific T cell response.

Ｂｉａｃｏｒｅによって測定される場合、可溶性ヒトＯＸ４０と、１ｎＭ以下のＫ_Ｄで結合する、請求項１から６のいずれか一項に記載の抗体。 When measured by Biacore, a soluble human OX40, it binds with the following _{K D} 1 nM, antibody of any one of claims 1 to 6.

ヒトＯＸ４０(配列番号２)の配列ＤＶＶＳＳＫＰＣＫＰＣＴＷＣＮＬＲ(配列番号１７８)の全てまたは一部分と結合する、請求項１から７のいずれか一項に記載の抗体。 The antibody according to any one of claims 1 to 7, which binds to all or part of the sequence DVVSSKSKCKPCTWCNLR (SEQ ID NO: 178) of human OX40 (SEQ ID NO: 2).

ＩｇＧ１アイソタイプである、請求項１から８のいずれか一項に記載の抗体。 The antibody according to any one of claims 1 to 8, which is of the IgG1 isotype.

ヒト抗体である、請求項１から９のいずれか一項に記載の抗体。 The antibody according to any one of claims 1 to 9, which is a human antibody.

請求項１から１０のいずれか一項に記載の抗体の重鎖および／または軽鎖可変領域をコードする、核酸。 A nucleic acid encoding the heavy and / or light chain variable region of the antibody according to any one of claims 1-10.

請求項１１に記載の核酸を含む、発現ベクター。 An expression vector comprising the nucleic acid according to claim 11.

請求項１２に記載の発現ベクターで形質転換された細胞。 A cell transformed with the expression vector according to claim 12.

請求項１から１０のいずれか一項に記載の抗体と、担体とを含む、組成物。 A composition comprising the antibody according to any one of claims 1 to 10 and a carrier.

１以上のさらなる治療薬をさらに含む、請求項１４に記載の組成物。 15. The composition of claim 14, further comprising one or more additional therapeutic agents.

１以上のさらなる治療薬が、抗ＰＤ１抗体、抗ＰＤ−Ｌ１抗体、ＣＴＬＡ−４抗体およびそれらの組み合わせからなる群から選択される、請求項１５に記載の組成物。 16. The composition of claim 15, wherein the one or more additional therapeutic agents are selected from the group consisting of anti -PD1 antibodies , anti-PD-L1 antibodies, CTLA-4 antibodies and combinations thereof.

癌を治療するための医薬の製造における、請求項１から１０のいずれか一項に記載の抗体の使用。 Use of an antibody according to any one of claims 1 to 10 in the manufacture of a medicament for treating cancer.

癌を治療するための医薬の製造における、請求項１４から１６のいずれか一項に記載の組成物の使用。 17. Use of a composition according to any one of claims 14 to 16 in the manufacture of a medicament for treating cancer.

癌が、子宮頸癌、結腸直腸癌、膀胱癌および卵巣癌からなる群から選択される、請求項１７または１８に記載の使用。 19. The use according to claim 17 or 18, wherein the cancer is selected from the group consisting of cervical cancer, colorectal cancer, bladder cancer and ovarian cancer.

ＯＸ４０と結合する単離されたモノクローナル抗体であって、
(ａ)それぞれ、配列番号１１〜１３の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号１４〜１６の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｂ)それぞれ、配列番号１９〜２１の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号２２〜２４の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｃ)それぞれ、配列番号１９〜２１の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号２５〜２７の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｄ)それぞれ、配列番号３１〜３３の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号３４〜３６の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｅ)それぞれ、配列番号３９〜４１の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号４２〜４４の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｆ)それぞれ、配列番号３９〜４１の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号４５〜４７の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｇ)それぞれ、配列番号５１〜５３の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号５４〜５６の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｈ)それぞれ、配列番号５９〜６１の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号６２〜６４の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｉ)それぞれ、配列番号６７〜６９の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号７０〜７２の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
(ｊ)それぞれ、配列番号７５〜７７の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号７８〜８０の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３であって、適宜、配列番号７６中のＡｓｐ−Ｇｌｙ配列が、異性化を受けていないアミノ酸配列と置換されている、配列、
(ｋ)それぞれ、配列番号７５〜７７の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号８１〜８３の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３、または
(ｌ)それぞれ、配列番号８７〜８９の配列を含む重鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３ならびにそれぞれ、配列番号９０〜９２の配列を含む軽鎖可変領域ＣＤＲ１、ＣＤＲ２およびＣＤＲ３配列
を含む、単離されたモノクローナル抗体。 An isolated monoclonal antibody which binds to OX40,
(a), respectively, the heavy chain variable region CDR1 comprising the sequence of SEQ ID NO: 11 to 13, CDR2 and CDR 3 of each Rabbi, the light chain variable region CDR1 comprising the sequence of SEQ ID NO: 14 to 16, CDR2 and CDR 3,
(b), respectively, SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 19 to 21, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 22 to 24 variable region CDR1, CDR2 and CDR 3,
(c), respectively, SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 19 to 21, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 25 to 27 variable region CDR1, CDR2 and CDR 3,
(d), respectively, the heavy chain variable region comprising the sequence of SEQ ID NO: 31 to 33 CDR1, CDR2 and CDR 3 of each Rabbi, the light chain variable region CDR1 comprising the sequence of SEQ ID NO: 34 to 36, CDR2 and CDR 3,
(e) Each SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 39-41, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 42 to 44 variable region CDR1, CDR2 and CDR 3,
(f), respectively, SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 39-41, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 45 to 47 variable region CDR1, CDR2 and CDR 3,
(g), respectively, SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 51 to 53, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 54 to 56 variable region CDR1, CDR2 and CDR 3,
(h), respectively, SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 59 to 61, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 62 to 64 variable region CDR1, CDR2 and CDR 3,
(i), respectively, SEQ ID NO: heavy chain variable region CDR1 comprising the sequence of 67 to 69, CDR2 and CDR 3 of each Rabbi, SEQ ID NO: light chain comprising the sequence of 70 to 72 variable region CDR1, CDR2 and CDR 3,
(j), respectively, each of the heavy chain variable region CDR1, CDR2 and CDR 3 rabbi comprising the sequence of SEQ ID NO: 75-77, there in the light chain variable region CDR1, CDR2 and CDR 3 comprising the sequence of SEQ ID NO: 78-80 A sequence wherein the Asp-Gly sequence in SEQ ID NO: 76 has been replaced with an amino acid sequence not subjected to isomerization, as appropriate.
(k), respectively, the heavy chain variable region CDR1 comprising the sequence of SEQ ID NO: 75 to 77, CDR2 and CDR 3 rabbi respectively, SEQ ID NO: light chain variable region CDR1 comprising the sequence of 81 to 83, CDR2 and CDR 3 or,
(l), respectively, each of the heavy chain variable region CDR1, CDR2 and CDR 3 rabbi comprising the sequence of SEQ ID NO: 87-89, comprising a light chain variable region CDR1, CDR2 and CDR3 sequences comprising the sequence of SEQ ID NO: 90 to 92 , Isolated monoclonal antibodies.

癌を治療するための医薬の製造における抗ＰＤ−１抗体ニボルマブと組み合わせる、請求項１から１０および２０のいずれか一項に記載の抗体の使用。21. Use of an antibody according to any of claims 1 to 10 and 20 in combination with the anti-PD-1 antibody nivolumab in the manufacture of a medicament for treating cancer.

癌を治療するための医薬の製造における抗ＣＴＬＡ−４抗体イピリムマブと組み合わせる、請求項１から１０および２０のいずれか一項に記載の抗体の使用。21. Use of an antibody according to any of claims 1 to 10 and 20 in combination with the anti-CTLA-4 antibody ipilimumab in the manufacture of a medicament for treating cancer.

癌を治療するための医薬の製造における抗ＰＤ−１抗体ニボルマブおよび抗ＣＴＬＡ−４抗体イピリムマブと組み合わせる、請求項１から１０および２０のいずれか一項に記載の抗体の使用。21. Use of an antibody according to any of claims 1 to 10 and 20 in combination with the anti-PD-1 antibody nivolumab and the anti-CTLA-4 antibody ipilimumab in the manufacture of a medicament for treating cancer.

請求項１３に記載の細胞を適した条件下で培養することおよび抗体を単離することを含む、ヒトＯＸ４０と結合する抗体を製造する方法。A method of producing an antibody that binds human OX40, comprising culturing the cells of claim 13 under suitable conditions and isolating the antibody.